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Structure-guided design and development of antivirals targeting BK polyomavirus capsid

We aim to rationally devise first-in-class compounds active against polyomaviruses which are linked to several diseases including cancer. In particular, BK polyomavirus (BKPyV) latently infects 80% of humans. Its reactivation in immunocompromised patients such as those undergoing kidney transplantation leads to severe complications including graft loss and acute renal failure in 5-10% cases. No approved drugs to combat BKPyV are currently available. Since PyVs lack conventional targets such as proteases, we focus on capsid assembly inhibitors like the ones under development for HIV and HBV. By using X-ray crystallography, we could structurally characterize the specific binding of multiple drug-like fragments to the major capsid protein VP1 of both BKPyV and a closely related JCPyV. The fragments bind in two novel assembly-relevant surface pockets. Combining the complementary expertise of the three applicants we will advance these fragment hits towards potent lead compounds via iterative fragment growth and linking, X-ray analysis, in vitro assembly inhibition, mutagenesis and cell-based viral replication assays.
Date:1 Oct 2018 →  30 Sep 2023
Keywords:polyomavirus, rational drug discovery, fragment-based drug design, antiviral agents, capsid assembly inhibition, X-ray crystallography, cell-based viral replication assays
Disciplines:Biochemistry and metabolism, Systems biology, Medical biochemistry and metabolism, Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences, Analytical chemistry, Medicinal and biomolecular chemistry, Molecular and cell biology, Plant biology, Biophysics